Investments in biomedical research have paid large dividends in the form of groundbreaking treatments for a host of diseases. Efforts to accelerate such benefits often assume there is a linear progression that begins with an understanding of basic biological principles, and then advances to therapeutic development, evaluation, and ultimately clinical application. As a result, many initiatives focus on the stages that follow discovery. Here, we propose to establish a Dartmouth Institute for Biomolecular Targeting (iTarget) that will infuse even early-stage mechanistic investigation with a sophisticated awareness of translational possibilities. This approach will ensure that knowledge of disease pathology provides focus and context to enhance the impact of even the most fundamental research. At the same time, it will target mechanistic investigations in directions that increase the probability of ultimate translational success. iTarget is structured (1) to accelerate the research productivity and scientific impact of four exceptional junior faculty members with interrelated interests in biomolecular target identification, validation, and inhibition; (2) to prvide a supportive framework for mentoring by experienced and committed senior faculty; (3) to develop essential shared research resources not available at Dartmouth or our regional IDeA partners and to facilitate access to existing cores; and (4) to recruit new faculty to the Institut. With faculty engagement from 10 departments across the Faculty of Arts and Sciences, Geisel School of Medicine, and Thayer School of Engineering, our initiative is truly multidisciplinary. Dartmouth's collegial and highly interactive faculty have outstanding strength in curiosity-based discovery, healthcare delivery and population-based outcomes analysis, and the university has made key investments in translational research. iTarget will thus benefit from natural research synergies that complement, but do not overlap with our programmatic partners. In return, iTarget will fill a critical role, bringing researchers together at the interface between basic and translational sciences. It will thus stimulate interdisciplinary and innovative research projects t address unmet therapeutic needs. It will also enhance the regional research infrastructure, providing cutting-edge strategies for generating proteins and other molecular targeting tools and for visualizing molecular interactions in purified systems and in cells. Dartmouth has also made a substantial institutional commitment to iTarget success and long-term sustainability, including the hiring of five new tenure-track faculty across campus. It will also provide program enrichment funds to support research infrastructure, scientific exchange, and a pilot project program to foster a vibrant intellectual community, recruit new members, and enhance the impact and funding competitiveness of all iTarget members. With experienced leadership, efficient administrative structures, and a compelling vision for a new paradigm that interweaves mechanistic and early- stage translational research, iTarget will develop a critical mass of extramurally funded investigators and thus thrive as a free-standing, nationally recognized Center of Biomedical Research Excellence at Dartmouth.